4-1BB is an inducible T cell receptor that belongs to the nerve growth factor receptor superfamily. This novel antigen is expressed on the surface of activated splenic T cells and thymocytes. The extracellular domain of this type I transmembrane protein is homologous to members of the nerve growth factor receptor superfamily. The cytoplasmic domain contains a sequence homologous to the binding site for T-cell-specific tyrosine kinase p56.sup.1ck.
The in vivo role of 4-1BB remains unclear, although increasing evidence indicates involvement as a signaling molecule in T cell activation. For example, cross-linking of 4-1BB with monoclonal antibody 53A2 on anti-CD3-stimulated T cells results in a 2 to 10-fold enhancement of T cell proliferation (Pollok et al. J. Immunol. 151:1255 (1993)). Furthermore, Zhou et al. (Immunol. Letters 41:177-184 (1994)) have demonstrated that 4-1BB is expressed on activated intestinal intra-epithelial T lymphocytes (IELS), and that activated IELS triggered with anti-4-1BB monoclonal antibody could enhance the level of IEL cytotoxicity against anti-CD4-secreting hybridoma cells. Cross-linking of anti-4-1BB antibody also enhanced proliferation of IELS.
At least two candidate ligands of 4-1BB have been identified. Chalupny et al. (Proc. Natl. Acad. Sci. U.S.A. 89:10360-10364 (1992)) used a soluble 4-1BB immunoglobulin fusion protein (4-1BB Rg) to demonstrate that 4-1BB binds to extracellular matrix protein (EMC). Goodwin et al. (Eur. J. Immunol. 23:2631 (1993)) reported the isolation of a cDNA for a ligand for murine 4-1BB (4-1-BB-L) that is a member of an emerging family of ligands with C-terminal amino acid homology which includes TNF, lymphotoxin (LT)-alpha and beta, CD40-L, CD27-L, CD30-L, and Fas-L.
The human analog (hu4-1BB) of murine 4-1BB and a human analog (hu4-1-BB-L) of murine 4-1-BB-L have been cloned (Alderson et al. Eur. J. Immunol. 24:2219-2227 (1994)). Both monoclonal antibody to hu4-1BB and cells transfected with hu4-1-BB-L induced a strong proliferative response in mitogen co-stimulated primary T cells.
Thus, a need exists for the development of antagonists of 4-1BB. The instant invention addresses this need and more.